The bcl-2 gene was discovered as typically involved in the t(14;18) chromosomal translocations observed in human follicular lymphoma (1-3). This chromosomal rearrangement results in deregulated high-level expression of the bcl-2 gene. In addition, Bcl-2 is also expressed at elevated levels in a variety of other tumors (4-6). The Bcl-2 protein suppresses apoptosis induced by a multitude of stimuli (7,8). Suppression of apoptosis by Bcl-2, while allowing cell survival, is characterized by growth arrest associated with Bcl-2 activity (40). Although bcl-2 was discovered as a candidate oncogene, conventional transformation assays indicate that it does not possess dominant oncogenic activity (9). It is therefore believed that unlike other oncogenes, bcl-2 contributes to oncogenesis primarily by extending cell viability, thereby perturbing the homeostatic mechanisms that control cell number and by providing an environment for other genetic changes (10).
In spite of a lack of detectable autonomous transforming activity, bcl-2 has been shown to synergize with c-myc in the generation of malignant cells (11). Since constitutive expression of c-myc induces apoptosis under certain conditions (12-14) that can be suppressed by Bcl-2 (14-16), it appears that the c-myc-cooperating oncogenic activity of bcl-2 may be related to its anti-apoptosis activity. In addition, Bcl-2 can also efficiently suppress apoptosis induced by tumor suppressor proteins such as p53 (17-21). This suggests that Bcl-2 may contribute to oncogenesis by suppressing apoptosis induced by oncogenes and tumor suppressor genes.
Although mutations within the Bcl-2 protein that permit proliferation of cells that would otherwise undergo total apoptosis could play a more direct role (as opposed to deregulated expression) in oncogenesis, thus far no such mutants have been identified in naturally arising tumors or under experimental conditions.